Graft devices and methods of fabrication

ABSTRACT

A graft device is provided comprising a flow conduit and a surrounding covering. The graft device is for connecting between a first body space and a second body space. In one embodiment, the flow conduit is a vein, such as a harvested saphenous vein, useful as an arterial graft, for example and without limitation, in a coronary artery bypass procedure. Also provided are methods of preparing a graft device and connecting the graft between a first body space and a second body space, such as the aorta and a location on an occluded coronary artery, distal to the occlusion.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase Application of InternationalApplication No. PCT/US2010/062487, filed on Dec. 30, 2010, which claimsthe benefit of and priority to U.S. Provisional Patent Application No.61/291,820, filed on Dec. 31, 2009. The disclosures of the aboveapplications are incorporated herein by reference in their entireties.

DESCRIPTION OF THE INVENTION

The present invention relates generally to graft devices for a mammalianpatient. In particular, the present invention provides graft devicescomprising a flow conduit and a covering.

BACKGROUND OF THE INVENTION

Coronary artery disease, leading to myocardial infarction and ischemia,is currently the number one cause of morbidity and mortality worldwide.Current treatment alternatives consist of percutaneous transluminalangioplasty, stenting, and coronary artery bypass grafting (CABG). CABGcan be carried out using either arterial or venous conduits and is themost effective and most widely used treatment to combat coronaryarterial stenosis, with nearly 500,000 procedures being performedannually. In addition there are approximately 80,000 lower extremitybypass surgeries performed annually. The venous conduit used for bypassprocedures is most frequently the autogenous saphenous vein and remainsthe graft of choice for 95% of surgeons performing these bypassprocedures. According to the American Heart Association, in 2004 therewere 427,000 bypass procedures performed in 249,000 patients. The longterm outcome of these procedures is limited due to occlusion of thegraft vessel or anastomotic site as a result of intimal hyperplasia(IH), which can occur over a timeframe of months to years.

Development of successful small diameter synthetic or tissue engineeredvascular grafts has yet to be accomplished and use of arterial grafts(internal mammary, radial, or gastroepiploic arteries, for example) islimited by the short size, small diameter and availability of thesevessels. Despite their wide use, failure of arterial vein grafts (AVGs)remains a major problem: 12% to 27% of AVGs become occluded in the firstyear with a subsequent annual occlusive rate of 2% to 4%. Patients withfailed arterial vein grafts (AVGs) can die or require re-operation.

IH accounts for 20% to 40% of all AVG failures within the first 5 years.Several studies have determined that IH develops, to some extent, in allmature AVGs and this is regarded by many as an unavoidable response ofthe vein to grafting. IH is characterized by phenotypic modulation,followed by de-adhesion and migration of medial and adventitial smoothmuscle cells (SMCs) and myofibroblasts into the intima where theyproliferate. In many cases, this response can lead to stenosis anddiminished blood flow through the graft. It is thought that IH can beinitiated by the abrupt exposure of the veins to the dynamic mechanicalenvironment of the arterial circulation.

For these and other reasons, there is a need for devices and methodswhich provide enhanced AVGs and other graft devices for mammalianpatients. Desirably the devices can improve long term patency andminimize surgical and device complications.

SUMMARY

Developing a reliable means to prevent the early events of the IHprocess and other luminal narrowing responses can contribute toimprovements in the outcome of arterial bypass and other graftprocedures. Therefore, provided herein is a method of mechanicallyconditioning and otherwise treating and/or modifying an arterial veingraft, or any flow conduit (e.g., living cellular structure) orartificial graft, typically, but not exclusively, in autologous,allogeneic, or xenogeneic transplantation procedures. To this end,provided herein is a method of wrapping a flow conduit, including,without limitation, a vein, artery, urethra, intestine, esophagus,trachea, bronchi, ureter, duct and fallopian tube. The graft is wrappedwith a covering such as a fiber matrix, typically with a biodegradable(also referred to as bioerodible or bioresorbable) polymer about acircumference of the flow conduit. In one non-limiting embodiment, thematrix is deposited onto flow conduit by electrospinning. In oneparticular non-limiting embodiment, the flow conduit is a vein, such asa saphenous vein, that is used, for example, in an arterial bypassprocedure, such as a coronary artery bypass procedure.

This new approach can have two potential applications. In the firstnon-limiting application, the matrix can be used as a peri-surgical toolfor the modification of vein segments intended for use as an AVG. Themodification of the vein or other tubular structure can be performed bytreating the structure at bedside, immediately after removal from thebody and just prior to grafting. In one non-limiting example, after thesaphenous vein is harvested, and while the surgeon is exposing thesurgical site, the polymer wrap can be electrospun onto the vein justprior to it being used for the bypass procedure.

The invention, in one aspect, features a graft device that includes aflow conduit and a covering. The flow conduit includes an inner surface,an outer surface, a proximal end, a distal end, and a lumentherethrough. The covering has a thickness and at least one channelextending from at least one of the inner surface or the outer surface ofthe flow conduit. The at least one channel extends through at least aportion of the thickness of the covering. The graft device isconstructed to provide connection between a first body space and asecond body space.

In some embodiments, the covering further includes an inner surface andan outer surface. The at least one channel can extend from the innersurface to the outer surface of the channel. In some embodiments, the atleast one channel has a diameter of approximately 100 microns to 200microns. The at least one channel can have a length of approximately 100microns to 1000 microns. In some embodiment, the at least one channel isconfigured and arranged to induce angiogenesis. The at least one channelcan comprise a circuitous route. The at least one channel can comprise arelatively linear route. The relatively linear route can be laser cut.In some embodiments, the at least one channel is constructed andarranged to approximate one or more properties of the vasa vasorem of avessel. The at least one channel can be created after the covering isapplied to the flow conduit. The at least one channel can be createdwhile the covering is applied to the flow conduit. In some embodiments,the covering is constructed and arranged to support an anastomoticconnection. The covering can be constructed and arranged to support ananastomotic connector.

According to an aspect of the invention, a graft device includes atubular flow conduit and a covering. The tubular flow conduit includesan inner wall, an outer wall, a proximal end, a distal end, and a lumenfrom the proximal end to the distal end. The tubular flow conduit ispositioned proximate the flow conduit, such as proximate the innerand/or outer walls of the flow conduit. The graft device is constructedand arranged for connection between a first body space and a second bodyspace.

In some embodiments, the tubular flow conduit comprises tissue. Numerousforms of tissue, such as tissue selected from the group consisting of:bone; skin; eustachian tube; artery; vein; urethra; lympathic duct;nasal channel; intestine; esophagus; ureter; urethra; trachea; bronchi;duct; fallopian tube; and combinations of these, can comprise the flowconduit. Tissue can be from a patient receiving the graft device(autologous tissue), from another being of the same species (allogeneictissue), or tissue from a species different than the patient (xenogeneictissue). The tubular flow conduit cam be a hollow tissue structure, suchas a tissue structure selected from the group consisting of: eustachiantube; artery; vein; urethra; intestine; esophagus; ureter; urethra;trachea; fallopian tube; and combinations of these. The tubular flowconduit can be cultured tissue, such as tissue grown around or within atubular scaffold, or tissue grown flat and subsequently formed into atube. Cultured tissue can be grown in-situ, such as within the body ofthe patient intended to receive the graft device.

In some embodiments, the tubular flow conduit comprises artificialmaterial, solely or in combination with living tissue. Numerous forms ofartificial materials can be used, such as materials selected from thegroup consisting of: polytetrafluoroethylene (PFFE); expanded PTFE(ePTFE); polyester; polyvinylidene fluoride/hexafluoropropylene(PVDF-HFP); silicone; and combinations thereof.

The covering can be placed to surround the outer wall of the tubularflow conduit, the inner wall of the tubular flow conduit, or both. Thecovering can be restrictive, applying a force resistant to radialexpansion of the tubular flow conduit, such as by applying a force toinitial radial expansion (e.g. when the covering is applied in contactwith the tubular flow conduit), or by applying a force after a fixedamount of radial expansion occurs (e.g. when the covering has an innerdiameter slightly larger than the outer diameter of the flow conduit).In some embodiments, the tubular flow conduit is a harvested vein, andthe covering is applied in a manner compressing the natural innerdiameter of the vein, such as compressing to a diameter approximating anartery being bypassed.

The covering can comprise one or more materials, such as one or morepolymers. The polymers can be natural or synthetic polymers, or blendsof natural and synthetic polymers. Typical polymers include but are notlimited to: silk, chitosan, collagen, elastin, alginate, cellulose,polyalkanoates, hyaluronic acid, gelatin; or combinations of these. Thecovering can be applied to the flow conduit while the flow conduit has amandrel (e.g. a straight or a curved mandrel) inserted through at leasta portion of its lumen.

The covering can comprise a helical spiral, such as a spiral that isuncoiled, expanding its inner diameter to be easily inserted over thetubular flow conduit. The covering can be radially stretched, afterwhich the tubular flow conduit can be inserted and the covering relaxed.The covering can include a cylindrical braid, such that longitudinalshortening of the covering causes its inner diameter to expand. Thecovering can comprise a wrapped sheet, such as a sheet formed into atube after which the flow conduit is inserted, or a sheet that iswrapped around the flow conduit while being formed into a tube. Thecovering can comprise a tube with a slit along at least a portion of itslength. The slit can be matched edge to edge or overlapped around thetubular flow conduit. The slit can be sealed, such as with an adhesive(e.g., fibrin glue), energy (e.g., heat, light or ultrasound energy);and combinations of these. The covering can be constructed and arrangedto shrink, such as a radial constriction caused by exposure to heat,light, or a polymerization process.

The covering can include a wrapped fiber, such as an electrospun fiber,or one or more fiber types supplied on one or more spools, and can bewrapped by hand or with a braiding or other wrapping machine. Thewrapped fiber can be overlapped over other fibers, and can includeattachment points between one or more fibers or between a fiber and thetubular flow conduit. Attachment points can be at the end of a fiber, ora cross-tie between two fiber mid portions. Attachment points caninclude fusion of two or more fibers such as with the application ofheat, ultrasound or other melting or welding energy. Attachment pointscan be achieved through the application of a knot or an adhesive such asfibrin glue. Attachment points can be achieved through solvent bonding.Wrapped fibers can be applied in a weave, such as a weave of multiplefibers of similar or dissimilar materials of construction. Typical fibermaterials include but are not limited to: silk; polyurethane; PCL; PEUU;PVDF-HFP; and combinations of these. A braid of multiple fibers, such asa fiber braid applied on a spool, can be wrapped about the flow conduit.

The covering can be applied to the flow conduit by dipping the flowconduit one or more times in a liquid material configured to solidifyover time. The covering can be applied to the flow conduit using a tool,such as a brush (e.g., a paint brush). Liquid covering materials can beapplied with a mandrel inserted into the flow conduit. In someembodiments, an anastomotic connector includes multiple filaments thatare braided or otherwise wrapped around the flow conduit, such as with abraiding machine, the covering comprising the wrapped filaments.

The covering can be biodegradable, such as a covering comprising amaterial that has a biodegradation rate that is based on the amount ofstress applied to the covering. The covering can include asemi-permeable membrane surrounding a biodegradable structure, andapplied stress can increase permeability of the membrane such as toincrease biodegradation. The covering can include microcapsules withporosity proportional to applied stress, the microcapsules releasing abiodegradation inhibitor or accelerator.

The covering can elude an agent, such as a drug. The elution rate canchange over time, such as a covering in which oxygen tension determinesrelease of an angiogenic factor, for example a covering in which reducedtension reduces the amount of VEGF released.

The graft device can include a circular cross section such as a circularcross section of relatively constant or varying diameter from itsproximal end to its distal end. The graft device can include, along atleast a portion of its length, a non-circular cross section such as anelliptical cross section. The covering can be attached to the flowconduit, such as by knitting with a suture or other filaments or with anadhesive. The graft device can have a linear bias or a non-linear bias.In embodiments in which the graft device has a non-linear bias, thenon-linear biased geometry can be based on a patient image, such as animage acquired with equipment selected from the group consisting of:X-ray; magnetic resonant imaging device (“MRI”); computed tomographyscanning device (“CT-scan”); nuclear magnetic resonance device (“NMR”);ultrasound device; digital camera (e.g. a charge-coupled device (“CCD”)camera); film camera; and combinations of these. In embodiments in whichthe graft device has a non-linear bias, a non-linear mandrel can beinserted into the flow conduit prior to application of the covering,causing a resilient, non-linear bias. A collapsible mandrel, such as aninflatable mandrel or furled mandrel, can be used to ease removal afterthe covering is applied.

The covering can include one or more channels, such as one or morechannels that extend from the inner wall to the outer wall of thecovering. Channels can be relatively linear or include tortuous orotherwise circuitous geometries. Channels can be created during and/orafter application of the covering to the flow conduit. Channel diameterscan be about 100 to about 200 microns, and channel lengths can be about100 to about 1000 microns.

The covering can include two or more layers. In some embodiments, athree layer covering includes a middle layer that is constructed andarranged to biodegrade prior to any significant biodegradation of theother two layers.

In some embodiments, the first body space is an aorta and the secondbody space is a coronary artery. The graft device can be attached tothree or more body spaces, in a serial grafting scheme, such as with aconnection at the flow conduit's proximal end, distal end and a thirdlocation between the flow conduit's proximal end and distal end. Thethird location can be at a location along the flow conduit including anopening, such as a side branch ostium in embodiments in which the flowconduit is a harvested blood vessel.

The graft device can include a reinforced portion near the proximal ordistal ends of the tubular flow conduit. The reinforcement can include areinforced covering, such as a thickened or otherwise reinforcedcovering proximate the proximal or distal ends. The graft device caninclude one end that is modified to include, or be attachable to, ananastomotic clip.

The graft device can include a mandrel, such as a conductive mandrelused to apply the covering to the flow conduit in an electrospinningprocess. The mandrel can have a multi-planar geometry, such as ageometry matching the geometry of placement of the graft device. Themandrel can be plastically deformable, such as to be formed by aclinician during a surgical implantation procedure. The mandrel can beconstructed and arranged to transition from a rigid to a flexible state,and/or from a flexible state to a rigid state, such as a mandrelconstructed of a material selected from the group consisting of: a lowmelting point metal such as indium; a shaped memory metal; a shapedmemory polymer; a liquid crystal that changes rigidity when current isapplied; and combinations of these.

The invention, in another aspect, features a method of creating a graftdevice. A tubular flow conduit is selected. The flow conduit comprisesan inner wall, an outer wall, a proximal end, a distal end, and a lumentherethrough. A covering is applied proximate the flow conduit. The flowconduit can be placed around a mandrel, such as a mandrel which isshaped to match a portion of a patient's anatomy. The mandrel can beshaped prior to and/or during the implantation procedure. The mandrelcan be shaped based on a patient image.

The covering can comprise fibers, such as fibers supplied on spools orfibers created during an electrospinning process. Fiber from multiplespools (e.g., similar or dissimilar fibers) can be applied proximate theflow conduit. The spooled fiber can be applied by hand or by a machinesuch as a braiding machine. The fiber can be applied in a cross-hatch orother weave pattern, and can be applied in one or more passes across theflow conduit. One or more fiber ends, or mid portions of a fiber, can befixed to the flow conduit or another fiber portion, such as fixationwith energy (e.g., to melt the fiber), solvent (e.g., to solvent bondfibers together), or adhesive (e.g., fibrin glue).

The covering can be a liquid material applied to the flow conduit andthen solidified or partially solidified. The liquid covering can beapplied in a dipping process, or through use of a tool such as a brushor spray tool. The covering can be cross-linked after application.

The covering can be stretched or expanded prior to application proximatethe flow conduit. In some embodiments, the covering is a helix which isunwound to radially expand, after which it is positioned proximate theflow conduit. In another embodiment, the covering is a cylindricalbraid, and the covering is longitudinally shortened, after which it ispositioned proximate the flow conduit. In some embodiments, the coveringincludes a tube with a slit along at least a portion of its length, andthe slit's width is extended after which the covering is positionedproximate the flow conduit, such as when the flow conduit is insertedinto the slit.

The flow conduit can be placed onto a mandrel prior to the placing ofthe covering proximate the flow conduit. The mandrel can be amulti-planar mandrel, such as a three dimensional mandrel created basedon a patient image.

The covering can be shrunk after application of the covering, such as byexposure to heat, light or a polymerization process. The covering can bemodified such as to increase the porosity of the covering. The graftdevice can be modified such as to cut one or more ends of the graftdevice, such as a cut at an oblique angle. An anastomotic connector canbe added to the graft device, such as a connector added prior to orafter applying the covering proximate the flow conduit. The anastomoticconnector can be attached to the covering and/or the flow conduit, or toa location between the covering and the flow conduit.

One or more channels can be created in a portion of the device, such asduring and/or after application of the covering. The channels can extendthrough the covering and/or through the flow conduit. The channels canbe relatively linear or have a circuitous path, and can be created usinga laser or etching process.

The invention, in another aspect, features a method of creating a graftdevice. A patient image is produced, and the graft device is createdbased on the patient image. The graft device can comprise a flow conduitand covering proximate the flow conduit. The flow conduit can be placedon a mandrel, such as a mandrel based on the patient image. The coveringcan be applied to the flow conduit with the patient image based mandrelinserted into the flow conduit. The mandrel can have one or moregeometric parameters based on the patient image. The parameters can beselected from the group consisting of: length; shape, diameter, andcombinations of these.

The invention, in another aspect features a method of creating a graftdevice. A three dimensional mandrel is produced, and a graft device iscreated over the three dimensional mandrel. The graft device cancomprise a flow conduit and covering proximate the flow conduit. Theflow conduit can be placed on a mandrel, such as a mandrel based on thepatient image. The covering is applied to the flow conduit with thepatient image based mandrel inserted into the flow conduit. The mandrelcan have one or more geometric parameters based on the patient image.The parameters can be selected from the group consisting of: length;shape, diameter, and combinations of these.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate various embodiments of thepresent invention, and together with the description, serve to explainthe principles of the invention. In the drawings:

FIGS. 1a and 1b illustrate side and end sectional views, respectively,of a graft device including a flow conduit and a covering, consistentwith the current invention;

FIG. 2 illustrates a side sectional view of a graft device including aflow conduit with inner and outer covering portions, and a securingfilament, consistent with the current invention;

FIG. 3 illustrates a side sectional view of a graft device including anon-linear bias, consistent with the current invention;

FIG. 4a illustrates a perspective view of a sheet of covering material,consistent with the current invention;

FIG. 4b illustrates a flow conduit with an inserted mandrel beingcovered with the sheet of covering material of FIG. 4a , consistent withthe current invention;

FIGS. 4c and 4d illustrate end and side views, respectively, of a graftdevice, including an adhesive seal along the edges of the covering,consistent with the present invention;

FIG. 5 illustrates a side sectional view of a bioreactor device;consistent with the present invention;

FIGS. 6a and 6b illustrate side and end sectional views, respectively,including a flow conduit surrounded by a covering with a void areabetween the flow conduit and covering, consistent with the presentinvention;

FIG. 7a illustrates an end sectional view of a flow conduit, consistentwith the present invention;

FIG. 7b illustrates an end sectional view of a covering, including aninner diameter less than the outer diameter of the flow conduit of FIG.7a , consistent with the present invention;

FIG. 7c illustrates an end sectional view of a graft device includingthe flow conduit of FIG. 7a surrounded by the covering of FIG. 7b ,consistent with the present invention;

FIG. 8a illustrates a side view of a helical covering, consistent withthe present invention;

FIG. 8b illustrates a side view of the helical covering of FIG. 8apartially unwound to increase the diameter of the covering, consistentwith the present invention;

FIG. 8c illustrates a side view a flow conduit with an inserted mandrelhaving been inserted into the partially unwound helical covering of FIG.8b , consistent with the present invention;

FIG. 8d illustrates a side view of a graft device including the assemblyof FIG. 8c after the helical covering has been rewound to the diameterof FIG. 8a , consistent with the present invention;

FIG. 9a illustrates a side sectional view of a cylindrically braidedcovering, consistent with the present invention;

FIG. 9b illustrates a side sectional view of the covering of FIG. 9aafter a force has been applied to each end to cause the diameter of thecovering to increase, consistent with the present invention;

FIG. 9c illustrates a side sectional view a flow conduit having beeninserted into the expanded diameter covering of FIG. 9b , consistentwith the present invention;

FIG. 9d illustrates a side sectional view of a graft device includingthe assembly of FIG. 9c after the covering diameter has been reduced,consistent with the present invention;

FIG. 10a illustrates a perspective view of a covering including alongitudinal slit, consistent with the present invention;

FIG. 10b illustrates a perspective view of a flow conduit with aninserted mandrel having been inserted through the slit of the coveringof FIG. 10a , consistent with the present invention;

FIG. 10c illustrates a side view of a graft device including theassembly of FIG. 10b after the covering diameter has been reduced and anadhesive applied to an edge of the longitudinal slit, consistent withthe present invention;

FIGS. 11a and 11b illustrate a method of making a graft device includingmultiple spools arranged to supply elongate fibers that arecircumferentially wrapped around a flow conduit with an insertedmandrel, consistent with the present invention;

FIG. 11c illustrates a side, partial sectional view of a graft devicefabricated with fibers from the multiple spools of FIGS. 11a and 11b ,consistent with the present invention;

FIGS. 12a, 12b and 12c illustrate a series of sequential flow conduitdipping steps used in the fabrication of yet another embodiment of agraft device, consistent with the present invention;

FIG. 12d illustrates an end view of a two piece mandrel with anelliptical cross section and a split outer portion and used in thefabrication steps of FIGS. 12a, 12b and 12c , consistent with thepresent invention;

FIG. 12e illustrates and end view the graft device fabricated using thedip method of FIGS. 12a, 12b and 12c and the mandrel of FIG. 12d ,consistent with the present invention;

FIGS. 13a and 13b illustrate a series of sequential material applicationsteps used in the fabrication of a graft device, consistent with thepresent invention;

FIG. 13c illustrates a side partial sectional view of the graft devicefabricated using the material application method of FIGS. 13a and 13 b;

FIG. 14 illustrates a graft device including multiple channels,consistent with the present invention;

FIG. 14a illustrates a magnified view of a portion of the graft deviceof FIG. 14;

FIG. 15a illustrates a side sectional view of a graft device including athree layer covering, consistent with the present invention;

FIG. 15b illustrates a side sectional view of the graft device of FIG.15a after one layer of the covering has biodegraded, consistent with thepresent invention;

FIG. 16 illustrates a side view of a heart and aorta of a mammalianpatient with a graft device attached to multiple vessels in a serialconnection scheme, consistent with the present invention;

FIG. 17a illustrates a side view of an anastomotic connector includingmultiple fibers extending from an end, consistent with the presentinvention;

FIG. 17b illustrates a side view of a flow conduit, consistent with thepresent invention;

FIG. 17c illustrates a method of fabricating a graft device, including adevice for weaving the fibers of the anastomotic connector of FIG. 17aaround the flow conduit of FIG. 17b , consistent with the presentinvention;

FIG. 18a illustrates a side sectional view of a non-linear mandrelsurrounded by a graft device, consistent with the present invention;

FIG. 18b illustrates a side view of an electrospinning instrument withthe non-linear mandrel and graft device of FIG. 18a , consistent withthe present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

Reference will now be made in detail to the present embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. Wherever possible, the same reference numbers will be usedthroughout the drawings to refer to the same or like parts.

Provided herein is a graft device including a flow conduit and covering,such as a graft device for connection between a first body space and asecond body space. The flow conduit can comprise tissue, such asautologous, allogeneic, or xenogeneic tissue, including, withoutlimitation: vein; artery; urethra; intestine; esophagus; ureter;trachea; bronchi; duct tissue; fallopian tube; or combinations of these(meaning the entire structure or a portion of those tissues). The flowconduit can also be a tissue engineered vascular graft, comprised of acovering material (biological- or synthetic-based) that is seeded withadult differentiated cells and/or undifferentiated stem cells, orunseeded. The covering can be treated with synthetic, biological, orbiomimetic cues to enhance anti-thrombogenicity or selective ornon-selective cell repopulation once implanted in vivo. Alternatively oradditionally, the flow conduit can include an artificial, non-tissue,structure, such as polytetrafluoroethylene (PTFE); expandable PTFE(ePTFE); polyester; polyvinylidene fluoride/hexafluoropropylene(PVDF-HFP); silicone; and combinations of these. The flow conduit canhave a relatively uniform cross section, or a cross section that varies(e.g. in diameter or cross sectional geometry) along the length of theflow conduit. Additional graft devices, systems and methods are alsodescribed in applicant's co-pending U.S. Provisional Patent ApplicationSer. No. 61/286,820, filed Dec. 16, 2009, entitled “Graft Devices andMethods for Use,” which is incorporated by reference herein in itsentirety.

Also provided is a method of creating a graft device by modifying atubular flow conduit through the application of a covering. One or morefibers, typically supplied on spools, can be wrapped around the flowconduit. A fiber matrix can be applied to the flow conduit, such as viaan electrospinning process. A liquid covering, such as a liquid polymer(a polymer solution, a polymer suspension, or a polymer melt) or otherliquid material, can be applied to the flow conduit in liquid(non-fibrous) form, which then solidifies or partially solidifies overtime. The flow conduit can be dipped into the liquid material, or theliquid material can be applied to the flow conduit with a tool such as abrush or a spraying device. Typical polymers include natural polymers,synthetic polymers, and blends of natural and synthetic polymers. Forexample and without limitation, natural polymers include silk, chitosan,collagen, elastin, alginate, cellulose, polyalkanoates, hyaluronic acid,or gelatin. Natural polymers can be obtained from natural sources or canbe prepared by synthetic methods (including by recombinant methods) intheir use in the context of the technologies described herein.Non-limiting examples of synthetic polymers include: homopolymers,heteropolymers, co-polymers and block polymers or co-polymers.

As used herein, the descriptor “flow conduit” does not referspecifically to a geometrically perfect tube having a constant diameterand a circular cross-section. It also embraces tissue and artificialconduits having non-circular and varying cross sections, and can have avariable diameter, and thus any shape having a contiguous wallsurrounding a lumen (that is, they are hollow), and two openings intothe lumen such that a liquid, solid or gas can travel from one openingto the other.

The covering typically is substantially or essentially contiguous aboutan internal or external wall of a flow conduit, meaning that thecovering forms a continuous, supportive ring on a surface and about acircumference of a portion, but not necessarily over the entire surface(e.g., length) of the flow conduit. The covering can be “restrictive”,meaning that the covering is in substantial contact with the outersurface of the flow conduit, or the covering can be narrowly spaced andproximate to the outer surface of the flow conduit (e.g. to restrictafter an initial unrestricted expansion). The covering can also be“constrictive”, meaning that the diameter of the flow conduit is reducedby the application of the covering. Restrictive coverings can be used toreinforce, restrict, hinder and/or prevent substantial circumferentialexpansion of the flow conduit, such as when the graft device is used asa bypass graft and is exposed to arterial pressure; or otherwise whenthe flow conduit is radially expanded. The degree of restriction by thecovering typically is such that when exposed to internal pressure, suchas typical arterial pressures, the flow conduit is prevented fromdistending to the extent that would occur without such restriction.Constrictive coverings can be used to match the internal diameter of theflow conduit, to the internal diameter of the target tissue beingconnected by the flow conduit. For example, quite often a vein beingused as a coronary artery bypass graft has a considerably largerinternal diameter than the target coronary artery being bypassed. Inorder to reduce flow disturbances, it is advantageous to match theinternal diameter of the graft (flow conduit) to the internal diameterof the stenosed coronary artery. The covering can be durable ortemporary, such as when the restrictive nature of a biodegradablecovering can decline over time. The covering can have a relativelyuniform cross section, or a cross section that varies along the lengthof the covering.

The covering can be applied to a flow conduit which has either acylindrical or non-cylindrical mandrel inserted in its lumen. Mandrelsare typically constructed and arranged to be removed from the graftdevice of the present invention without damaging the flow conduit or anyother portion of the graft device. The mandrel can comprise anexpandable tube, such as a furled tube or other radially expandablestructure, such that the mandrel can be unfurled or otherwise radiallyconstricted for atraumatic removal from the flow conduit of the graftdevice. The mandrel can transform from a rigid state to a flexiblestate, and vice versa.

The mandrel can be relatively straight, or can have a non-lineargeometry, such as a three dimensional geometry intended to matchanatomical locations of a patient, such as an anatomical topographyproximate two or more intended anastomotic connections for the graftdevice. The mandrel can be a malleable or otherwise deformable structurewhich is shaped during a patient open surgical procedure. Alternatively,the mandrel can be fabricated based upon one or more patient imagescreated during an imaging procedure, such as an imaging procedureselected from the group consisting of: X-ray; MRI, CT scan, NMR,ultrasound, CCD camera; film camera; and combinations of these.

In coverings applied to a flow conduit with an electrospinning process,an electrically conductive mandrel, for example a rod that is formed ofa conductive material such as stainless steel, can be placed inside atubular conduit, such as a vein, and polymer fibers deposited about thecircumference of at least a portion of the tissue by rotation or othermovement of the mandrel, movement of the nozzles supplying the fiber,and/or movement of the electrical field directing the fibers toward themandrel. A thickness of the covering can be controlled by adjusting thechemical or physical properties of the polymer solution to be deposited,increasing the infusion rate of the polymer solution, and/or adjustingduration of the electrospinning. Use of more viscous polymer compositioncan result in thicker fibers, requiring less time to deposit a coveringof a desired thickness. Use of a less viscous polymer composition canresult in thinner fibers, requiring increased deposition time to deposita covering of a desired thickness. The thickness of the covering andfibers within the covering affects the speed of biodegradation of thecovering. Biodegradation can also be varied by altering the surfacefinish or porosity of the fibers, which can be altered by using solventsor diluents that evaporate at varying rates or also by adding purifiersto the solution, such as immiscible fluids, emulsified particles orundissolved solids that can be later dissolved, thereby creating pores.These parameters are optimized, depending on the end-use of thecovering, to achieve a desired or optimal physiological effect.Thickness can be varied along the length of a target in a regular orirregular fashion, such as in creating a target that is thicker at oneor both ends, in the center or as with a location-dependent symmetricalor asymmetrical thickness. In another particular embodiment, thethickness is varied by moving an electrospinning nozzle back and forthslowly, near a specific circumferential location, thereby depositingmore material proximate to that area. In yet another particularembodiment, covering thickness is determined by the thickness of theflow conduit, such as when the covering is thicker at a circumferentialportion of the flow conduit that is thinner than other circumferentialportions of the flow conduit.

Electrospinning can be performed using two or more nozzles, wherein eachnozzle can be a source of a different polymer solution. The nozzles canbe biased with different biases or the same bias in order to tailor thephysical and chemical properties of the resulting non-woven polymericmesh. Additionally, multiple different targets (e.g. mandrels) can beused. When the electrospinning is to be performed using a polymersuspension, the concentration of the polymeric component in thesuspension can also be varied to modify the physical properties of thematrix. For example, when the polymeric component is present atrelatively low concentration, the resulting fibers of the electrospunnon-woven mesh have a smaller diameter than when the polymeric componentis present at relatively high concentration. Without any intention to belimited by this theory, it is believed that lower concentrationsolutions have a lower viscosity, leading to faster flow through theorifice to produce thinner fibers. One skilled in the art can adjustpolymer solution chemical and physical properties and process parametersto obtain fibers of desired characteristics, including fibers whosecharacteristics change along the length or width of the target.

Coverings can be constructed and arranged in a manner specific to apatient morphological or functional parameter. These parameters can beselected from the group consisting of: vessel size such as diameter,length, and/or wall thickness; taper or other geometric property of aharvested vessel or vessel intended for anastomotic attachment; size andlocation of one or more side branch ostium or antrum within theharvested vessel; patient age or sex; vessel elasticity or compliance;vessel vasculitis; vessel impedance; specific genetic factor or trait;and combinations of these.

Coverings of arterial vein grafts can be processed in a way to achieve acertain blood flow rate or shear stress within the treated arterial veingraft. In a typical configuration, shear stress within the arterial veingraft is between about 2-30 dynes/cm², preferably about 12-20 dynes/cm².Coverings can be processed in a way to control the oxygen, nutrients, orcellular permeabilities between the extravascular tissues and theabluminal surface of the treated hollow tissue. Such permeabilitiesdepend on the covering chemical and physical properties, the pore sizedistribution, porosity, and pore interconnectivity. Generally, oxygen,nutrients, and cellular (e.g., endothelial cells, endothelial progenitorcells, etc.) permeability are required to improve the treated hollowtissue in vivo remodeling and healing process. To this end, the poresize range is typically between about 10 and about 1000 microns,preferably between about 200 and about 500 microns, and the porosityrange typically between about 50% and about 95%, preferably betweenabout 60% and about 90%. The pores preferably are highly interconnectedso that a relatively straight path along the radial direction of thefiber matrix can be traced from most of the pores across the totalthickness of the matrix. Polymers used are typically hydrophilic.

Radial restriction and constriction of saphenous vein grafts has beenachieved with stent devices placed over the vein prior to anastomosingthe graft to the targeted vessels. The devices of the present inventionprovide numerous advantages over the stent approaches. The devices ofthe present invention can have one or more parameters easily customizedto a parameter of the harvested vessel and/or another patient parameter.The covering can be customized to a harvested vessel parameter such asgeometry, such as to reduce the vein internal diameter to producedesired flow characteristics. The covering can be customized to a targetvessel parameter (e.g., the aorta and diseased artery), such as to becompatible with vessel sizes and/or locations. The covering can bemodified to simplify or otherwise improve the anastomotic connections,such as to be reinforced in the portion of the device that isanastomosed (e.g., portion where suture and/or clips pass through)and/or to protrude beyond the length of the flow conduit and overlapother members connected to the graft device.

The devices of the present invention can be made to a wide array oflengths during the procedure, without the need for cutting, such as thecutting of a stent device, which might create dangerously sharp edges.The covering is applied to the flow conduit in a controlled, repeatablemanner, by an apparatus such as an electrospinning instrument. The endsof the covering are atraumatic, avoiding tissue damage at theanastomotic sites. In addition, the coverings of the present inventionare easily and atraumatically removable, such as to apply anothercovering. Stent devices are applied manually by a clinician, requiresignificant manipulation which could cause iatrogenic damage, haveissues with reproducibility and accuracy limitations, and are difficultto reposition or remove, particularly without damaging the harvestedvessel.

As used herein, the term “polymer composition” is a compositioncomprising one or more polymers. As a class, “polymers” includeshomopolymers, heteropolymers, co-polymers, block polymers, blockco-polymers and can be both natural and synthetic. Homopolymers containone type of building block, or monomer, whereas co-polymers contain morethan one type of monomer. For example and without limitation, polymerscomprising monomers derived from alpha-hydroxy acids includingpolylactide, poly(lactide-co-glycolide),poly(L-lactide-co-caprolactone), polyglycolic acid,poly(dl-lactide-co-glycolide), poly(l-lactide-co-dl-lactide); monomersderived from esters including polyhydroxybutyrate, polyhydroxyvalerate,polydioxanone and polygalactin; monomers derived from lactones includingpolycaprolactone; monomers derived from carbonates includingpolycarbonate, polyglyconate, poly(glycolide-co-trimethylene carbonate),poly(glycolide-co-trimethylene carbonate-co-dioxanone); monomers joinedthrough urethane linkages, including polyurethane, poly(ester urethane)urea elastomer.

A biodegradable polymer is “biocompatible” in that the polymer anddegradation products thereof are substantially non-toxic, includingnon-carcinogenic, non-immunogenic and non-sensitizing, and are clearedor otherwise degraded in a biological system, such as an organism(patient) without substantial toxic effect. Non-limiting examples ofdegradation mechanisms within a biological system include chemicalreactions, hydrolysis reactions, and enzymatic cleavage. Biodegradablepolymers include natural polymers, synthetic polymers, and blends ofnatural and synthetic polymers. For example and without limitation,natural polymers include silk, fibrin, chitosan, collagen, elastin,alginate, cellulose, polyalkanoates, hyaluronic acid, or gelatin.Natural polymers can be obtained from natural sources or can be preparedby synthetic methods (including by recombinant methods) in their use inthe context of the technologies described herein. Non-limiting examplesof synthetic polymers include: homopolymers, heteropolymers, co-polymersand block polymers or co-polymers.

The polymer or polymers typically will be selected so that it degradesin situ over a time period to optimize mechanical conditioning of thetissue. Non-limiting examples of useful in situ degradation ratesinclude between about 2 weeks and about 1 year, and increments of about1, 2, 4, 8, 12, and 24 weeks therebetween. Biodegradation can occur atdifferent rates along different circumferential and/or axial portions ofthe covering. A biodegradation rate of the polymer covering can bemanipulated, optimized or otherwise adjusted so that the coveringdegrades over a useful time period. For instance, in the case of acoronary artery bypass, it is desirable that the covering dissolves overabout 12 hours or more, typically two weeks or more, so as to preventsubstantial sudden stress on the graft. The polymer degrades over adesired period of time so that the mechanical support offered by thepolymer covering is gradually reduced over that period and the veinwould be exposed to gradually increasing levels of circumferential wallstress (CWS).

The biodegradable polymers useful herein also can be elastomeric.Generally, any elastomeric polymer that has properties similar to thatof the soft tissue to be replaced or repaired is appropriate. Forexample, in certain embodiments, the polymers used to make the wrap arehighly distensible. Non-limiting examples of suitable polymers includethose that have a breaking strain of from about 100% to about 1700%,more preferably between about 200% and about 800%, and even morepreferably between about 200% and about 400%. Further, it is oftenuseful to select polymers with tensile strengths between about 10 kPaand 30 MPa, more preferably between about 5 MPa and 25 MPa, and evenmore preferably between about 8 and about 20 MPa. In certainembodiments, the elastic modulus calculated for physiologic levels ofstrain is between about 10 kPa to about 100 MPa, more preferably betweenabout 500 kPa and about 10 MPa, and even more preferably between about0.8 MPa and about 5 MPa.

In a preferred embodiment, the graft devices of the present inventionperform or is produced by one or more parameters listed in Table 1immediately herebelow, typically with an electrospinning or othermaterial application process:

TABLE 1 Category Typical and Preferred Settings Covering Material:Typical: Applicable Polymers PEUU (2-30%); PCL (5-35%); PCL:PGA/PLLA(5-35% - from 80:20 to 50:50); PCL:PLLA (5-35% - from 80:20 to 50:50);PVDF; PVDF-HFP; Silk-Fibroin Preferred: PEUU (5-10%); PCL (5-15%);PCL:PGA (5-15% - 50:50); PCL:PLLA (5-15% - 50:50); PVDF; PVDF-HFP; Silk-Fibroin Covering Process Typical: Solvents (e.g., electrospin HFIP;DMSO; Chloroform; THF; DMF; Dichloromethane; solvents, solvents forDMAC, Dioxane; Toluene; Water; Acetone; Methanol; dipping or brushPropanol; Ethanol; Lithium Bromide; Aqueous Solutions application)(alkaline/acidic) Preferred: HFIP; DMF; THF; DMSO; Water More PreferredHFIP; Water Covering Thickness Typical: 50-1000 μm Preferred: 50-200 μmMore Preferred: 50-150 μm Covering O₂ Permeability Typical 10⁻¹⁰ to 10⁻⁶(cm² mL O₂)/(s mL mmHg) Covering Porosity Typical 50%-95% Preferred85%-90% Covering Average Pore Typical Size 0.001-2.0 mm Preferred0.10-1.0 mm Also Preferred 0.005-0.020 mm Covering Compliance Typical(measured in arterial-like 2-100 × 10⁻⁴ mmHg⁻¹ conditions 70-110 mmHg)Preferred (arterial blood applications) 2-15 × 10⁻⁴ mmHg⁻¹ CoveringAnastomotic Typical Retention Force (e.g., 1-10 N suture retention)Covering Circumferential Typical Elastic Modulus (Static 0.5-2.0 MPaElastic Modulus E) Preferred 0.8-2.0 MPa Covering ViscoelasticityTypical (Dynamic Elastic between 1-fold and 2-fold E Modulus G) CoveringDegradation Typical Kinetics (in vivo greater than 2 weeks completeresorption) Preferred linear reduction over 3-6 months Covering HardnessTypical polymer Brinnell Scale between 5 and 40 Covering RoughnessTypical 2-50 μm

As used herein, the terms “comprising,” “comprise” or “comprised,” andvariations thereof, are meant to be open ended. The terms “a” and “an”are intended to refer to one or more.

As used herein, the term “patient” or “subject” refers to members of theanimal kingdom including but not limited to human beings.

As used herein, a “fiber” comprises an elongated, slender, thread-likeand/or filamentous structure.

As used herein, a “matrix” is any two- or three-dimensional arrangementof elements (e.g., fibers), either ordered (e.g., in a woven ornon-woven mesh) or randomly-arranged (as is typical with a mat of fiberstypically produced by electrospinning).

A polymer “comprises” or is “derived from” a stated monomer if thatmonomer is incorporated into the polymer. Thus, the incorporated monomerthat the polymer comprises is not the same as the monomer prior toincorporation into a polymer, in that at the very least, certainterminal groups are incorporated into the polymer backbone. A polymer issaid to comprise a specific type of linkage if that linkage is presentin the polymer.

Referring now to FIGS. 1a and 1b , side sectional and end sectionalviews, respectively, of a graft device of the present invention areillustrated. Graft device 100, biased in a relatively linear bias asshown, includes lumen 150 from first end 101 to second end 102. Graftdevice 100 also includes flow conduit 140 which is surrounded on itsouter wall 141 by covering 120. Alternatively or additionally, covering120 can surround the inner wall 142 of flow conduit 140. Covering 120can be a radially restrictive covering, such as a radially restrictivecovering comprising a fiber matrix applied to flow conduit 140 during anelectrospinning process. A restrictive covering can be used to limitradial expansion of flow conduit 140, such as when device 100 is used asa bypass graft in a cardiac bypass procedure. Similarly, the covering120 can be radially constrictive, such as a radially constrictivecovering comprising a fiber matrix applied to flow conduit 140 during anelectrospinning process. Covering 120 can be radially stretched prior toapplication around flow conduit 140, such as with a tube expandingdevice. Covering 120 can be radially shrunk after placement around flowconduit 140, such as when covering 120 is a material constructed andarranged to radially shrink with the application of heat, light orpolymerization. Flow conduit 140 can include any tissue or artificialstructure, such as has been described hereabove, or can include bothtissue and artificial materials.

Graft device 100 is constructed and arranged to be placed between afirst body space, such as a source of oxygenated arterial blood such asthe aorta, and a second body space, such as a location distal to anoccluded artery, such as an occluded coronary artery. In a typicalembodiment, flow conduit 140 is a harvested vessel, such as a harvestedsaphenous vein graft (SVG). Graft device 100 can be processed after theapplication of covering 120. This processing can include cutting one orboth of ends 101 and 102, such as to cut to a particular length. Thecutting can be performed orthogonally or at an oblique angle (e.g. aspatulation cut), such as to improve creation and/or longevity of ananastomosis. The processing can include modifying one or both of flowconduit 140 and covering 120, such as to modify a surface or otherparameter of flow conduit 140 or covering 120. Porosity can be modified,such as with a laser drilling device or mechanical puncturing device.Surface properties can be modified, such as with a laser or otheretching process.

Covering 120 can have one or both of its end portions (portionsproximate end 101 and end 102) modified or otherwise of differentconstruction than the mid portion of covering 120. In a particularembodiment, at least one end portion of covering 120 is modified tosupport an anastomotic connection such as a connection achieved withsuture, staples, or an anastomotic connector. The modification caninclude the end portions of covering 120 being thicker or thinner thanthe mid portion; the end portions being constructed of a differentmaterial or materials such as the inclusion of an increased tearresistant material such as the inclusion of a metal mesh; andcombinations of these.

Flow conduit 140 can be biodegradable or include one or morebiodegradable portions. Biodegradation of flow conduit 140 can be stressor strain dependent biodegradation. Stress or strain dependentdegradation (hereinafter “stress dependent degradation”) kinetics ofcovering 120 can be customized for a desired remodeling of flow conduit140, such as when flow conduit 140 is a harvested vessel such as aharvested saphenous vein graft. Stress based degradation can be usedsuch that degradation would occur or accelerate only when mechanicalsupport would be no longer desired (this degradation arrangement couldbe relatively continuous or triggered by a threshold). In certainembodiments, covering 120 is used to provide temporary mechanicalsupport to a tissue based flow conduit 140 that is subjected tosupra-physiologic conditions. The desired degradation mechanism would beconstructed and arranged as follows: device 100 is placed between afirst body space such as the aorta, and a second body space, such as acoronary artery. After this implantation, the initial levels of stressapplied to covering 120 are at a maximum as the underlying flow conduit140 (e.g. a harvested vessel) has not yet adapted (e.g. example wallshave not yet thickened) and has minimum contribution toward stressrelief. The initial degradation rate can be configured to be minimal atthis initial stage. As the tissue begins to remodel constructively inresponse to the increased stress (e.g. vessel tissue training), thestress relief provided by flow conduit 140 will be increased, resultingin lesser stress transmission to covering 120. Covering 120 isconstructed and arranged to trigger a mechanism by which the degradationof the material would be accelerated, and with increased degradationwould follow increased tissue training, consequential increaseddegradation, and so on.

In a particular embodiment, covering 120 is a matrix comprising apolymeric network possessing functional groups acting as part of apolymer backbone and/or as crosslinking molecules for the network. Thefunctional groups are designed to dissociate from the polymer in thepresence of naturally occurring enzymes in vivo. The functional groupsalso possess a receptor for a synthetic molecule (ligand) which isstored in microcapsules embedded at strategic locations, and with aspecific distribution, within the matrix. The wall of the microcapsulehas a permeability that is directly proportional to the level of stressor strain applied to the wall. A reaction is achieved where higherstress yields larger pores; larger pores yields higher permeability; andhigher permeability yields higher release of ligands. In the presence ofthe synthetic ligands released by the microcapsules, the receptor of thefunctional group creates a steric hindrance for the naturally occurringenzymatic cleavage resulting in a reduced degradation rate.

In one application, covering 120 with stress based biodegradationsurrounds a tissue based flow conduit 140 that is initially damaged butsubjected to physiologic demands and therefore in need of temporarysupport while the healing process takes place. In another embodiment, asemi-permeable membrane surrounds a biodegradable covering 120, and themembrane pores expand under stress to increase biodegradation.

Covering 120 can be constructed and arranged to have stress basedresponses other than biodegradation, such as chemical, biological, orother responses. Alternative or additional to degradation basedkinetics, covering 120 can achieve other response kinetics such as othermechanical response kinetics, electrical response kinetics, drug elutingkinetics, or another type of reaction kinetics. In one exemplaryapplication, graft device 100 is sensitized to the local levels ofoxygen tension that controls the kinetics of release of angiogenicfactors such as VEGF. Initially, low oxygen tension yields high VEGFrelease; high VEGF release yields high angiogenesis; high angiogenesisyields higher oxygen tension which then causes lower release of VEGF.

Referring now to FIG. 2, a side sectional view of a graft device of thepresent invention including a covering with inner and outer portions isillustrated. Graft device 100, biased in a relatively linear bias asshown, includes lumen 150 from first end 101 to second end 102. Graftdevice 100 also includes flow conduit 140 which is surrounded on itsouter wall 141 by covering first portion 120 a, and surrounded on itsinner wall 142 by covering second portion 120 b. Covering first portion120 a and covering second portion 120 b are fixedly secured to flowconduit 140 by filament 104, illustrated in a stitching patternreciprocally passing from the external surface of covering first portion120 a to lumen 150. In an alternative embodiment, filament 104 passesbetween covering first portion 120 a and flow conduit 140 withoutpassing through covering second portion 120 b. In another alternativeembodiment, filament 104 passes between flow conduit 140 and coveringsecond portion 120 b without passing through covering first portion 120a. Alternatively or additionally, an adhesive or other fixation devicecan be used to mechanically fix covering portion 120 a or coveringportion 120 b to flow conduit 140.

Referring now to FIG. 3, a side sectional view of a graft device of thepresent invention including a curvilinear bias is illustrated. Graftdevice 100, biased in the curvilinear bias as shown, includes lumen 150from first end 101 to second end 102. Graft device 100 also includesflow conduit 140 which is surrounded on its outer wall 141 by covering120. In a particular embodiment, the curvilinear bias of graft device100 is achieved by the application of covering 120 to flow conduit 140.The curvilinear bias can be achieved by inserting a curvilinear mandrel(not shown but described in detail in reference to FIGS. 18a and 18bherebelow), and applying covering 120 with flow conduit in thecurvilinear geometry of the inserted mandrel such that a curvilinearbias is achieved. The curvilinear orientation of graft device 100 can bedesirable to match a patient condition, such as the anatomical geometryof the area in which graft device 100 is to be placed. The curvilineargeometry can be based on a patient image, such as an image created by aninstrument selected from the group consisting of: X-ray; MRI, CT scan,NMR, Ultrasound, CCD camera; film camera; and combinations of these.

Covering 120 includes reinforced ends 121 a and 121 b. Ends 121 a and121 b have a thickness greater than the mid portion of covering 120,such that an anastomotic connection is reinforced, as has been describedabove. Ends 121 a and 121 b can have similar or dissimilar thicknesses.Alternatively or additionally, different materials can be used in ends121 a and 121 b, such as tear resistant materials. Ends 121 a and 121 bcan be configured to biodegrade, at similar or dissimilar rates to eachother and the mid portion of covering 120.

Referring now to FIGS. 4a through 4d , multiple views of a method forcreating a graft device of the present invention are illustrated. FIG.4a illustrates a perspective view of sheet 125. Sheet 125 can comprisetissue, such as cultured tissue, tissue engineered material, artificialmaterial, such as PTFE or one or more polymer materials described above,or combinations of these. FIG. 4b illustrates an end view of sheet 125partially rolled around flow conduit 140 which surrounds insertedmandrel 190. FIG. 4c illustrates an end view of covering 120, comprisingsheet 125 of FIG. 4b in a tubular geometry and fixedly attached alongits longitudinal edges with filament 104. Filament 104 is typically asuture or other biocompatible filament used to sew tissue and/orartificial materials together for medical implants or in medicalprocedures. Covering 120 circumferentially surrounds flow conduit 140with inserted mandrel 190. FIG. 4d illustrates a side view of graftdevice 100 of FIG. 4c . In subsequent steps, not shown, mandrel 190 isremoved, and device 100 placed between a first body space and secondbody space as has been described in detail above.

Referring now to FIG. 5, a side sectional view of a bioreactor device ofthe present invention is illustrated. Bioreactor 180 is constructed andarranged for cell culture. Cellular structures can be generated in oraround scaffolds, such as scaffolds implanted in the patient to receivethe graft device of the present invention, or a surrogate mammal orother member of the animal kingdom. The cellular structures can begenerated as a tube, flat plate, rolled tube or other structure, andused as the flow conduit of the present invention. The patient's bodycan be used as an “in vivo bioreactor” to grow living tissues as itprovides cells and the correct environment (temperature, pH, nutrients)to foster new tissue formation. For example, bioreactor 180 or anotherbiocompatible “template” such as a PTFE or a metal mandrel can beinserted into a body cavity (e.g., the abdominal cavity) for adetermined amount of time (e.g., a few days to a few weeks). Autologous,allogeneic or xenogeneic tissues can be generated. Advantages includethe natural foreign body response which tends to “encapsulate” an objectimplanted in an area with good vascularization.

Bioreactor 180 includes cell support scaffold 184 a and 184 b configuredto allow cellular growth thereupon. Bioreactor 180 further includesupper channel 185 a, middle channel 185 b and low channel 185 c, throughwhich an inoculum can be introduced, as well as cell nourishingnutrients. Each channel 185 a, 185 b and 185 c includes inlets 181 a,181 b and 181 c respectively. Each channel 185 a, 185 b and 185 cfurther includes outlets 182 a, 182 b and 182 c respectively. The first184 a and second 184 b cell support scaffolds each comprise at least onethree-dimensional porous matrix, such as a matrix containing non-wovenfibrous polyethylene terephthalate or a similar material. The firstscaffold 184 a is positioned within chamber 186 between upper channel185 a and middle channel 185 b. The second scaffold 184 b is positionedbetween middle channel 185 b and lower channel 185 c.

First scaffold 185 a and second scaffold 185 b can have similar ordissimilar thicknesses and can have similar or dissimilar porosities.These differences can be based on the type of cell being deposited andcultured in the particular matrix. Alternatively or additionally, inorder to influence movement of seeded cells into the or throughscaffolds 184 a and 184 b, at least one of the three channels 185 a, 185b and 185 c can contain a fluid having one or more cell growth factors,or other cell attractants or repellents. Specific cells can be selectedfrom a mixed population of cells and attracted into scaffold 184 aand/or 184 b for attachment and growth. Alternatively or additionally,at least one of the three channels 184 a, 185 b and 185 c can contain acell nourishing medium, such as a gel medium.

Bioreactor 180 preferably has a chamber 186 which is elongated, havingthe three channels 185 a, 185 b and 185 c extending through a lengthwiseextent of chamber 186. Each channel's inlet 181 a, 181 b and 181 c,respectively, is positioned at a first lateral periphery of chamber 186,and each channel's outlet 182 a, 182 b and 182 c, respectively, ispositioned at a second lateral periphery of chamber 186 and generallyopposite the first lateral periphery. First scaffold 184 a and secondscaffold 184 b can be separated from each other by non-scaffold material183, as shown in FIG. 5.

In typical use, bioreactor 180 includes chamber 186 wherein the middlechannel 185 b contains a fluid carrying a plurality of cell types,wherein the upper channel 185 a contains a fluid having one or morefactors effective for influencing migration of at least a first celltype from middle channel 185 b into the first scaffold 184 a, andwherein the lower channel 185 c contains a fluid having one or morefactors effective for influencing migration of at least a second celltype from middle channel 185 b into the second scaffold 184 b. It isunderstood that at least one of the three channels 185 a, 185 b and 185c contains an inoculum comprising cells.

Those skilled in the art will understand that the number of channels 185a, 185 b and 185 c, and/or scaffolds 184 a and 184 b can be increased.Multiple bioreactors 180 can be connected via a connector, such as toincrease cell culture productivity. A reservoir, not shown butpreferably including a fluid medium, can be connected to one or morebioreactors 180, such as to pump or otherwise deliver the flow mediumtherethrough. One or more valves, also not shown, can be included tocontrol the flow of the flow medium through one or more bioreactors 180.Those skilled will recognize that through the use of a sufficient numberof valves, the flow rate of fluid through of each channel can becontrolled appropriately for cell seeding, for cell growth and culture,and for cell removal from the bioreactor.

Referring now to FIGS. 6a and 6b , side and sectional views,respectively, of a graft device of the present invention configured fordelayed restriction of a flow conduit are illustrated. Graft device 100,biased in a relatively linear bias as shown, includes lumen 150 fromfirst end 101 to second end 102. Graft device 100 also includes flowconduit 140 which is surrounded on its outer wall 141 a by covering 120.Alternatively or additionally, covering 120 can surround the inner wall141 b of flow conduit 140. Separating outer wall 141 a and covering 120is space 103, sized to allow a fixed amount of expansion of flow conduit140 prior to applying a restrictive force to flow conduit 140. Space 103can be configured to ease insertion of flow conduit 140 into covering120. Covering 120 can be a temporary radially restrictive covering, suchas a biodegradable covering. Flow conduit 140 can include any tissue orartificial structure, such as has been described above, or can includeboth tissue and artificial materials. In an alternative embodiment,covering 120 is shrunk after placement around flow conduit 140, such asto reduce or eliminate space 103.

Referring now to FIGS. 7a through 7c , end views of a flow conduit, acovering, and a graft device, respectively, of the present invention areillustrated. FIG. 7a illustrates an end sectional view of a flow conduit140 with an outer diameter D1. FIG. 7b illustrates an end sectional viewof a covering 120 with an inner diameter D2, wherein D2 is less than D1.FIG. 7c illustrates an end sectional view of graft device 100 includingflow conduit 140 of FIG. 7a surrounded by covering 120 of FIG. 7b . Theouter diameter of flow conduit 140 has been reduced to diameter D2 dueto the radial constraint of covering 120. This diameter reduction can bechosen such that a predetermined inner diameter of flow conduit 140 isachieved, such as an inner diameter based on the pre-harvesting diameterof a saphenous vein graft used for flow conduit 140.

Referring now to FIGS. 8a through 8d , multiple views of a method forcreating a graft device of the present invention are illustrated. FIG.8a illustrates a side view of covering 120, a helical structure in itsrelaxed state with an inner diameter D1. FIG. 8b illustrates a side viewof covering 120 of FIG. 8a with its helical coil unwound such thatcovering 120 has increased inside diameter D2. FIG. 8c illustrates aside view of covering 120, maintained in an unwound state with theincreased internal diameter D2 of FIG. 8b , inserted over flow conduit140. Flow conduit 140 has been inserted over mandrel 190. In FIG. 8d ,covering 120 has been released or otherwise rewound to diameter D1 ofFIG. 8a , such that covering 120 contacts flow conduit 140, such as toradially constrict flow conduit 140. In subsequent steps, not shown,mandrel 190 is removed, and device 100 is placed between a first bodyspace and second body space as has been described in detail above. In analternative embodiment, mandrel 190 is removed prior to the diameterreduction of covering 120. In another alternative embodiment, flowconduit 120 is temporarily radially expanded, such as with a balloon orother elongate radial expansion device, without unwinding a helicalcoil, and placed around flow conduit 140. Covering 120 can beconstructed of biodegradable material or can include one or morebiodegradable portions.

Referring now to FIGS. 9a through 9d , multiple views of a method forcreating a graft device of the present invention are illustrated. FIG.9a illustrates a side view of covering 120, a cylindrically braidedstructure in its relaxed state with an inner diameter D1. FIG. 9billustrates a side view of covering 120 of FIG. 9a with a force Fapplied to its ends such that covering 120 has increased inside diameterD2. Covering 120 can include a biaxial cylindrical braid. Pushing on theends of covering 120 shortens its length and increases its diameter.Pulling on the ends of covering 120 causes lengthening as well as adecrease in diameter. The length is gained by reducing the angle betweenthe warp and weft threads of the braid at their crossing points, butthis reduces the distance between them and hence the circumference.

FIG. 9c illustrates a side view of covering 120, with force F maintainedon each end maintaining the increased internal diameter D2 of FIG. 9b ,inserted over flow conduit 140. In FIG. 8d , covering 120 has beenreleased (force F removed) to diameter D1 of FIG. 9a , such thatcovering 120 contacts flow conduit 140, such as to radially constrictflow conduit 140. Graft device 100 includes lumen 150 extending fromfirst end 101 and second end 102. In subsequent steps, not shown, device100 is placed between a first body space and second body space as hasbeen described in detail hereabove.

Referring now to FIGS. 10a through 10c , multiple views of a method forcreating a graft device of the present invention are illustrated. FIG.10a illustrates a side view of covering 120, a tubular structure withlongitudinal slit 122 along its length. In an alternative embodiment,slit 122 extends along a partial length of covering 120. FIG. 10billustrates a side view of covering 120 of FIG. 10a with flow conduit140 having been inserted through slit 122. Flow conduit 140 surroundsmandrel 190. In an alternative embodiment, slit 122 is pulled apart suchthat flow conduit 140 can be inserted into either end of covering 120.FIG. 10c illustrates a side view of mandrel 190 with device 100surrounding it. Slit 122 has been sealed along its length with adhesive106, preferably a fibrin glue or other biocompatible adhesive.Alternatively or additionally, slit 122 can be sewn together with sutureor other biocompatible filament. Alternatively or additionally, slit 122can be fixed together through the application of energy or exposure to asolvent. Slit 122 can be sealed by overlapping the two longitudinalsides of covering 120, the sealing performed with one or more of:adhesive such as fibrin glue; mechanical fasteners; application ofenergy such as heat, light or ultrasound energy; and exposure to acovering material solvent. Covering 120 can be radially shrunk, such asvia exposure to heat or light, or polymerization of covering 120. Insubsequent steps, not shown, mandrel 190 is removed, and device 100 isplaced between a first body space and second body space as has beendescribed in detail hereabove. In an alternative embodiment, mandrel 190is removed prior to the diameter reduction of covering 120.

Referring now to FIGS. 11a through 11c , multiple views of a method forcreating a graft device of the present invention are illustrated. FIG.11a illustrates a side view of flow conduit 140 with inserted mandrel190. Fibers 126 a and 126 b are being supplied by spools 127 a and 127b, respectively, and are being circumferentially disposed about theouter wall 142 of flow conduit 140. Fibers 126 a and 126 b can besimilar or dissimilar. In an alternative embodiment, a single fiber isused. The process can be performed in a sterile setting, such as anoperating room sterile area, or a sterilization step can be performedafter application of fibers 126 a and 126 b around flow conduit 140.FIG. 11b illustrates the view of FIG. 11a after fibers 126 a and 126 bhave substantially covered outer wall 142 of flow conduit 140. Bondingelement 129 is included to fixedly attach fibers 126 a and/or 126 banother portion of the same fiber, the other fiber, and/or flow conduit140. Bonding element can be included at multiple locations, to affix orcreate cross-ties between fibers 126 a and/or 126 b. Bonding element cancomprise one or more of: an adhesive such as fibrin glue or elastomericadhesive, one or more knots; and a melted or solvent bonded joint of thefibers.

Fibers 126 a and 126 b can be constructed of one or more materials suchas silk, polyurethane, PCL, PEUU, PVDF-HFP or other biocompatiblematerial manufactured in a filamentous structure, such as via wetspinning. Fibers 126 a and 126 b can be a braided fiber. Fibers 126 aand 126 b can be manually wrapped about flow conduit 140 or aninstrument, such as a braiding machine, can be used to spin mandrel 190and/or rotate spools 127 a and 127 b about flow conduit 140. Fibers 126a and 126 b can be applied in a woven or cross hatch geometry, andmultiple passes can be used to overlap the fibers.

In FIG. 11c , a side, partial sectional view of the graft deviceproduced in FIGS. 11a and 11b is illustrated. Covering 120 includes thewrapped fibers 126 a and 126 b. Graft device 100 includes lumen 150within flow conduit 140, through which one or more solids, liquidsand/or gases can flow.

Referring now to FIGS. 12a through 12c , multiple views of a method forcreating a graft device of the present invention are illustrated. FIG.12a illustrates a side view of flow conduit 140 including outer wall 141and inserted mandrel 190. Flow conduit 140 is positioned above areservoir 191 containing liquid covering material 128. Liquid coveringmaterial 128 can include numerous liquid polymers, elastomers, or otherliquid or suspension materials that are constructed and arranged forapplication of a biocompatible substance to a structure via a dippingprocess subsequent to which material 128 hardens or otherwisesolidifies. In a typical embodiment, liquid covering material 128 isselected from the group consisting of: a liquid silicone material, suchas a silicone gel such as Sylgard; a hyrdrogel such as a fibrin gel;gelatin; and combinations of these. FIG. 12b illustrates of side view ofthe flow conduit 140 of FIG. 12a having been partially immersed in theliquid covering material 128 of reservoir 191. FIG. 12c illustrates aside view of flow conduit 140 with inserted mandrel 190 once againpositioned above reservoir 191. Covering 120 has been formed, orpartially formed, during the dipping step of FIG. 12b . Additionaldipping steps can be performed, including but not limited to: switchingthe end of mandrel 190 that is held during the dip; rotating mandrel 190during a dip or between a first dip and a second dip; treating thedipped flow conduit 140 such as treating with light, heat, air, a crosslinking operation, and other exposures to cause liquid material 128 tosolidify; and combinations of these.

Referring additionally to FIGS. 12d and 12e , mandrel 190 comprises asplit outer portion 190 a and a continuous inner portion 190 b, bothcomprising a continuous, relatively elliptical cross section along theirlength. Mandrel portion 190 a is configured to radially expand whenmandrel portion 190 b is inserted therein. As shown in FIG. 12e , device100 of FIGS. 12c and 12e has a relatively uniform, elliptical crosssection along its length due to the geometry of mandrel 190. Theelliptical geometry can provide numerous benefits including but notlimited to a preferred bending moment of device 100. Mandrel 190 hasbeen removed from device 100 of FIG. 12e such as by first removing innerportion 190 b, allowing outer portion 190 a to radially collapse foratraumatic removal of outer portion 190 a from flow conduit 140. In analternative embodiment, mandrel 190 can be configured with a variedgeometry cross section, such as a circular or elliptical cross sectionwithin a major or minor axis that reduces along the length of device100, or an elliptical cross section that changes to a circular crosssection.

Referring now to FIGS. 13a and 13b , multiple views of a method forcreating a graft device of the present invention are illustrated. FIG.13a illustrates a side view of flow conduit 140 with outer wall 141 andinserted mandrel 190. Liquid covering material 128 is being applied toouter wall 141 with applicator tool 192 comprising a brush, roller orother tool adapted for applying a liquid to a surface. Liquid coveringmaterial 128 can include numerous liquid polymers, elastomers, or otherliquid or suspension materials that are constructed and arranged forapplication of a biocompatible substance to a structure via anapplicator tool subsequent to which material 128 hardens or otherwisesolidifies. In a typical embodiment, liquid covering material 128 isselected from the group consisting of: a liquid silicone material, suchas a silicone gel such as Sylgard; a hyrdrogel such as a fibrin gel;gelatin; and combinations of these. Covering 120 has been formed fromliquid material 128 during the application step of FIG. 13a . Additionalapplication steps can be performed, including but not limited to:switching the end of mandrel 190 that is held during the application ofliquid material 128; rotating mandrel 190; treating the flow conduit 140with applied covering 120 such as treating with light, heat, air, across linking operation, and other exposures to cause liquid material128 to solidify.

Referring additionally to FIG. 13c , covering 120 has a non-uniformsurface comprising a varied thickness along the length of graft device100. Graft device 100 includes lumen 150 within flow conduit 140,through which one or more solids, liquids and/or gases can flow.

Referring now to FIGS. 14 and 14 a, a side sectional view and anexploded sectional view, respectively, of a graft device of the presentinvention are illustrated. Graft device 100, biased in a relativelylinear bias as shown, includes lumen 150 from first end 101 to secondend 102. Graft device 100 also includes flow conduit 140 which issurrounded on its outer wall or surface 141 by covering 120.Alternatively or additionally, covering 120 can surround the inner wallor surface 142 of flow conduit 140. Covering 120 can be a radiallyrestrictive covering, such as a radially restrictive covering comprisinga fiber matrix applied to flow conduit 140 during an electrospinningprocess. A restrictive covering can be used to limit radial expansion offlow conduit 140, such as when device 100 is used as a bypass graft in acardiac bypass procedure. Covering 120 can be radially stretched priorto application around flow conduit 140, such as with a tube expandingdevice. Covering 120 can be radially shrunk after placement around flowconduit 140, such as when covering 120 is a material constructed andarranged to radially shrink with the application of heat, light or apolymerization process. Flow conduit 140 can include any tissue orartificial structure, such as has been described hereabove, or caninclude both tissue and artificial materials.

As shown in FIG. 14a , an exploded view of graft device 100 at circleC1, covering 120 includes multiple channels 124 which have acurvilinear, tortuous geometry extending from the outer surface ofcovering 120 to the outer wall or surface 141 of flow conduit 140.Alternatively or additionally, numerous other configurations of channelscan be included such as configurations selected from the groupconsisting of: relatively linear channels; channels that have at leastone fluid connection point with another channel; channels that do notextend fully from the outer surface of covering 120 to the outer wall orsurface 141 of flow conduit 140, channels that extend into a mid portionof flow conduit 140, channels that extend to inner wall 142 of flowconduit 140; at least one channel 124 that extends from at least one ofthe inner surface 142 or the outer surface 141 of the flow conduit 140where the channel 124 extends through at least a portion of a thicknessof the covering 120; and combinations of these. Channels 124 can becreated after application of covering 120 to flow conduit 140, duringapplication of covering 120 to flow conduit 140 (e.g. during anelectrospinning application of covering 120), or prior to application ofcovering 120 to flow conduit 140. Channels 124 can be created with oneor more cutting or drilling tools, such as lasers, mechanicalpenetrators, chemical etchants, and the like. Channels 124 can beconstructed and arranged to induce angiogenesis, to mimic the vasavasorem of a vessel wall, or otherwise cause a physiologic responsebeneficial to the long term efficacy of an implanted device 100.Channels typically have a diameter between about 100 and about 200microns, and a length range from about 100 to about 1000 microns.

Channels 124 can be positioned, sized and oriented using numeroustechniques including the placement of hollow tubes which surround thechannel, and the use of solid filaments which dissolve or are otherwiseremoved leaving channels in their place. In a particular embodiment,channels 124 include hollow tubes with straight, bent, or tortuousgeometries, and with various sizes and lengths. The tubes can be madefrom materials that are resistant to the solvent that is used to preparethe polymer solution for creating covering 120. In one particularembodiment, the tubes are constructed from a salt based material thatcan be leached away after covering 120 is applied to flow conduit 140.After the tubes are leached away, channels 124 remain. Channels 124 canbe included in flow conduit 140 prior to the application of covering 120(e.g., via electrospinning, spraying, dipping, brushing, etc.) byapplying these miniature tubes onto the surface of flow conduit 140,such as by applying with adhesive to maintain attachment and/ororientation. Channels 124 can be arranged in a random pattern or caninclude some preferential orientations (e.g., radial). After thecovering 120 is deposited around flow conduit 140, previously coveredwith the miniature tubes, the resulting deposited external layer,covering 120, will be a composite of two materials. The first materialis the deposited material, acting like the resin in a compositematerial. The second material is the miniature tubes, channels 124,acting like the fibers in a composite material. Covering 120 nowincludes many independent internal channels (as many as the number oflittle tubes). If the size and chemistry of these channels aresupportive of cells adhesion and migration (e.g. some cytokines orgrowth factor internal treatment that performs as a chemo-attractant),channels 124 can sprout blood vessels coming from the surroundingtissues toward flow conduit 140. If channels 124 are radially oriented,the path required to cross the covering 120 by new capillary formationis minimized. The miniature tubes can be configured to dissolve orbiodegrade over time, or can remain in place for at least a portion ofthe implant life of device 100.

Alternatively or additionally, leachable or fast degrading miniaturefilament-type rods (e.g. salt based rods) can be applied to flow conduit140 prior to application of covering 120. These rods instead of actingas tunnels per se, dissolve (e.g., salt leaching) and leave channels 124in covering 120 in a geometry similar to the space previously occupiedby the rods.

In an alternative embodiment, channels in covering 120 or anotherportion of graft device 100 are eliminated or reduced, such as throughthe application of an adhesive or a relatively non-porous material, orcompression or melting of areas surrounding the channels.

Referring now to FIG. 15a , a side sectional view and an end portion ofa graft device of the present invention is illustrated. Graft device100, biased in a relatively linear bias as shown, includes lumen 150within flow conduit 140 and extending to end 102. Flow conduit 140includes a three-layer covering comprising first layer 120 a, secondlayer 120 b and third layer 120 c. First layer 120 a and third layer 120c are circumferentially attached at each device end (end 102 shown), byadhesive 106, typically a fibrin or elastomeric glue. As shown in FIG.15b , second layer 120 b is constructed and arranged to dissolve,biodegrade, or otherwise no longer be present when first layer 120 a andthird layer 120 c are still intact. Second layer 120 b can provide atransport barrier between first layer 120 a and third layer 120 c for alimited period of time. Second layer 120 b can release chemoattractantsto one or more of: flow conduit 140, lumen 150, first layer 120 a, thirdlayer 120 c, or a tissue location exterior to device 100. After secondlayer 120 b is partially or fully removed, first layer 120 a and/orthird layer 120 c can extend into the space previously occupied bysecond layer 120 b, such as when at least a portion of flow conduit 140extends radially out, or at least a portion of third layer 120 c extendsradially in. Removal of second layer 120 b can cause the radialresistance of device 100 to modify over time. In an alternative oradditional embodiment, either or both first layer 120 a and third layer120 c can be configured to biodegrade over time, such as both firstlayer 120 a and third layer 120 c biodegrading at similar or dissimilarrates.

Referring now to FIG. 16, a side view of a heart and aorta of amammalian patient with a graft of the current invention attached tomultiple vessels in a serial connection scheme is illustrated. Graftdevice 100 includes first end 101 and second end 102. First end 101 isfluidly attached to the Aorta at connection 170 a, an end to sideanastomosis. A mid portion of graft device 100 is fluidly attached tothe left anterior descending artery (LAD) at connection 170 b, a side toside anastomosis. Second end 102 is fluidly attached to a diagonal ofthe LAD, D1, at connection 170 c, another end to side anastomosis.Device 100 is serially attached to the patient's Heart such that bloodflows from the Aorta into the LAD at connection 170 b, and into D1 atconnection 170 c. An advantage of the serial connection scheme shown inFIG. 16 is that the flow through the portion of device 100 betweenconnection 170 a and 170 b is increased due to the additional flow intoconnection 170 c. Higher flow has been shown to improve patency of veingrafts in patients in numerous clinical studies. In one embodiment,graft device 100 comprises a covering surrounding a vessel graft, suchas a harvested saphenous vein graft. The serial connection 170 b is madeat a location along the vein graft that previously included the ostiumto or from a side branch of a harvested artery or vein. In other words,the opening in the side of the vein graft becomes the anastomotic site,yielding improved flow conditions. Device 100's covering is created suchas to keep the side branch site intact. A hole punch or other tool canbe used to make the corresponding opening in the covering. Numerouscombinations of anastomosis and serial connections with one or moredevices 100, such as a first device connected in an end to sideanastomosis to a second device, can be used to achieve a desired flowconfiguration.

The curvilinear geometry of device 100 of FIG. 16 can be predeterminedbased on intended anastomotic connection sites, such as during an opensurgical procedure or prior to that in a patient imaging procedure ashas been described in detail hereabove. Device 100 can have had a curvedmandrel inserted into the vessel graft prior to application of thecovering, such as to bias device 100 in the shown geometry.

Referring now to FIGS. 17a through 17c , multiple views of a method forcreating a graft device of the present invention are illustrated. FIG.17a illustrates a side view of anastomotic connector 160 which includesframe 161, flange 162, and multiple attached fibers 126 of the presentinvention extending from frame 161. FIG. 17b illustrates a side view offlow conduit 140 inserted over mandrel 190 and including outer wall 141.FIG. 17c illustrates a side view of an instrument creating a graftdevice of the present invention including anastomotic connector 160 ofFIG. 17a and flow conduit 140 of FIG. 17b . Flow conduit 140 has beeninserted within frame 161 of connector 160. Mandrel 190 has beenremovably coupled at each end to braiding instrument 193. Fibers 126have been attached to braiding instrument 193, such that operation ofbraiding instrument 193 causes fibers 126 to be woven about or otherwisewrapped around outer wall 141 of flow conduit 140. In a particularembodiment, portions of fibers 126 are affixed to outer wall 141 oranother portion of fiber 126 such as to prevent unwrapping of fibers126. Fibers 126 can be fixed with one or more mechanisms such as amechanism selected from the group consisting of: melted fibers such asfibers melted with the application of energy such as heat or applicationof a solvent; fibers fixed with an adhesive such as fibrin glue; fibersfixed with one or more knots or other frictionally engagingarrangements; and combinations of these.

Referring now to FIG. 18a , a side sectional view of a graft device ofthe present invention with a curvilinear configuration is illustrated.Graft device 100 is inserted over curvilinear mandrel 190 and includesflow conduit 140 and surrounding covering 120. The curvilinearconfiguration of mandrel 190 and graft device 100 can be based onpatient anatomy, such as the anatomy proximate the aorta and one or moreoccluded arteries to be bypassed. The curvilinear configuration can bebased on a visual or other analysis performed in an open surgicalprocedure, or a visualization procedure performed prior to surgery, suchas an image created with a visualization apparatus as has been describedin detail hereabove. Mandrel 190 can be malleable or otherwiseshapeable, such that the mandrel can be shaped during the surgicalprocedure in the sterile setting. Mandrel 190 can be configured totransition between flexible and rigid configurations, such as a mandrelselected from the group consisting of: mandrels including gallium whichcan be made rigid at exposure to 30° C. and below; mandrels includingshaped memory alloys or polymers configured to change from flexible torigid on demand; liquid crystals that are configured to stiffen with theapplication of current; and combinations of these. In a particularembodiment, mandrel 190 is used in an electrospinning process to applycovering 120 and mandrel 190 includes electrically conductive materialused in the electromagnetic field generation of the electrospinningprocess. In an alternative embodiment, a vasoconstrictor can be used toconstrict flow conduit 140 around mandrel 190.

Referring additionally to FIG. 18b , a side view of an electrospinninginstrument with inserted nonlinear mandrel and graft device of FIG. 18a, all of the present invention, is illustrated. Electrospinning unit 200is rotatably or fixedly attached to mandrel 190 which is surrounded byflow conduit 140. Electrospinning unit includes base 203 upon whichmotor 201 is fixedly mounted. Rotating frame 202 is rotatably mounted tobase 203 such that nozzles 210 and lasers 220 can rotate about mandrel190, such as with rotation of rotating frame 202 via motor 201, rotationof mandrel 190 via motor 201, or both. Conduit 212 is configured tosupply energy and/or one or more electrospinning materials, such aselectrical or laser energy to lasers 220 and/or polymer and/or othersolutions to nozzles 210. Rotating connector 211 allows rotation offrame 202 and/or mandrel 190 while maintaining fluid sealed attachmentto conduit 212. The configuration of electrospinning instrument 200allows both straight and curved mandrels 190 to be inserted therein.Lasers 220 can be used during the electrospinning process to removeand/or modify portions of electrospun fibers. Lasers 220 can also beused to modify flow conduit 140, such as prior to beginning ofelectrospinning, or modify covering 120 after the electrospinningprocess has completed. Additionally or alternatively, lasers 220 can beused to mark flow conduit 140, indicating the direction of venous flowwhen flow conduit 140 is for example, a saphenous vein. Numerous otherconfigurations of electrospinning instrument 190 or other fiberapplication instruments can be used to apply fibers to a flow conduitwithout departing from the spirit and scope of this application.

While the graft device of the present invention has mainly beendescribed for connections between two vessels, such as the aorta and acoronary artery, numerous other body locations can be used fortransporting gases, liquids or solids from a first body location to asecond body location. While the flow conduit of the present inventionhas been mainly described as a harvested vessel such as a saphenous veingraft, numerous other tubular and other luminal structures can be used.

While the preferred embodiments of the devices and methods have beendescribed in reference to the environment in which they were developed,they are merely illustrative of the principles of the inventions.Modification or combinations of the above-described assemblies, otherembodiments, configurations, and methods for carrying out the invention,and variations of aspects of the invention that are obvious to those ofskill in the art are intended to be within the scope of the claims. Inaddition, where this application has listed the steps of a method orprocedure in a specific order, it can be possible, or even expedient incertain circumstances, to change the order in which some steps areperformed, and it is intended that the particular steps of the method orprocedure claim set forth herebelow not be construed as beingorder-specific unless such order specificity is expressly stated in theclaim.

We Claim:
 1. A method of creating a graft device for a patient themethod comprising: shaping a mandrel based on one or more geometricparameters of a patient image; placing a living tubular conduitharvested from the patient over the shaped mandrel; applying a coveringover the living tubular conduit to form the graft device; and removingthe shaped mandrel from the graft device, wherein the graft devicecomprises the one or more geometric parameters of the patient image. 2.The method of claim 1, wherein the living tubular conduit comprises aneustachian tube, an artery, a vein, a urethra, an intestine, anesophagus, a ureter, a trachea, a fallopian tube, or combinationsthereof.
 3. The method of claim 1, wherein the patient image is producedby an instrument comprising X-ray, MRI, Ct-Scan; NMR, Ultrasound, CCDCamera, film camera, or combinations thereof.
 4. The method of claim 1,wherein a cross section of the graft device varies from a proximal endto a distal end.
 5. The method of claim 1, wherein the coveringcomprises a polymer.
 6. The method of claim 1, wherein the applyingcomprises electrospinning a fiber matrix over the living tubularconduit.
 7. The method of claim 6, wherein the electrospun fiber matrixcomprises a polymer.
 8. The method of claim 1, wherein the applyingcomprises performing multiple passes along the living tubular conduit.9. The method of claim 1, wherein the covering resists radial expansionof the living tubular conduit.
 10. The method of claim 1, wherein thecovering initially allows radial expansion of the living tubular conduitand subsequently resists radial expansion of the living tubular conduit.11. The method of claim 10, wherein the initial radial expansion occursduring the applying.
 12. The method of claim 1, further comprisingattaching the graft device between an aorta and a coronary artery of thepatient.
 13. The method of claim 1, wherein the shaped mandrel comprisesa conductive material.
 14. The method of claim 1, wherein the shapedmandrel is plastically deformable.
 15. The method of claim 1, whereinthe shaped mandrel transitions one or more times between flexible andrigid configurations.
 16. The method of claim 1, wherein the shapedmandrel comprises a non-circular cross section.
 17. The method of claim1, wherein the patient image is of an anastomotic connection site. 18.The method of claim 1, wherein the patient image is of an anatomicalarea proximate to an aorta and one or more occluded arteries.
 19. Themethod of claim 1, wherein the patient image is obtained from avisualization procedure on the patient.
 20. The method of claim 1,wherein the patient image is obtained prior to or during a surgicalprocedure.
 21. The method of claim 1, wherein the one or more geometricparameters comprise a length, a shape, a diameter, or combinationsthereof.
 22. The method of claim 1, wherein the covering is arestrictive covering or a constrictive covering.
 23. The method of claim1, further comprising collapsing the shaped mandrel before the removing.24. The method of claim 23, wherein the shaped mandrel comprises aninner portion and an outer portion and wherein the inner portion of theshaped mandrel is removed before collapsing the outer portion of theshaped mandrel.